Department of Biomaterials, Science, and Technology, TechMed Centre, Targeted Therapeutics Section, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
Laboratory Pathology East Netherlands (LabPON), Hengelo, The Netherlands.
FASEB J. 2019 May;33(5):6609-6621. doi: 10.1096/fj.201802336R. Epub 2019 Feb 26.
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest tumor due to its highly abundant tumor stroma. Pancreatic stellate cells (PSCs) are considered precursor cells of cancer-associated fibroblasts (CAFs), which induce tumor progression, invasion, and metastasis. In this study, we investigated the role of integrin subunit α (ITGA) 11, the receptor for collagen type I, in tumor stroma interaction. Clinical sample analysis showed that ITGA11 was overexpressed by CAFs in PDAC stroma, as shown with colocalization immunostaining with α-smooth muscle actin. In contrast, there was no expression in healthy pancreas. Public transcriptomic data confirmed a reduced expression of ITGA11 in healthy pancreas and adjacent nontumoral tissues compared with human tumor tissues. Primary human PSCs (hPSCs) activated with either TGF-β or pancreatic cancer cell (PANC-1)-conditioned medium (CM) resulted in the significant up-regulation of ITGA11 and various CAF markers. Furthermore, short hairpin RNA (shRNA)-mediated stable ITGA11 knockdown (shITGA11) in hPSCs significantly inhibited TGF-β- and PANC-1 CM-mediated activation at both gene and protein levels of extracellular matrix, cytokines, and adhesion molecules. Additionally, shITGA11 hPSCs had a reduced migration and contractility compared with shRNA control (shCTR) PSCs. Furthermore, we investigated the effect of ITGA11 on the paracrine effects of hPSCs. Interestingly, the CM from shITGA11 hPSCs, activated with either TGF-β or PANC-1 CM, caused tumor cells to migrate and invade lesser compared with their counterpart, activated shCTR PSCs. In summary, this study presents ITGA11 as an interesting stromal therapeutic target that plays a crucial role in the regulation of the differentiation of PSCs into CAFs and paracrine effects.-Schnittert, J., Bansal, R., Mardhian, D. F., van Baarlen, J., Östman, A., Prakash, J. Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer.
胰腺导管腺癌 (PDAC) 因其丰富的肿瘤基质而成为最致命的肿瘤。胰腺星状细胞 (PSC) 被认为是癌相关成纤维细胞 (CAF) 的前体细胞，它诱导肿瘤的进展、侵袭和转移。在这项研究中，我们研究了整合素亚基 α (ITGA) 11 的作用，ITGA11 是胶原蛋白 I 的受体，在肿瘤基质相互作用中起作用。临床样本分析表明，在 PDAC 基质中，CAF 过表达 ITGA11，α-平滑肌肌动蛋白免疫染色显示共定位。相比之下，在健康胰腺中没有表达。公共转录组数据证实，与人类肿瘤组织相比，健康胰腺和相邻非肿瘤组织中 ITGA11 的表达降低。用 TGF-β 或胰腺癌细胞 (PANC-1) 条件培养基 (CM) 激活的原代人 PSC (hPSC) 导致 ITGA11 和各种 CAF 标志物的显著上调。此外，hPSC 中的短发夹 RNA (shRNA) 介导的 ITGA11 稳定敲低 (shITGA11) 显著抑制了 TGF-β 和 PANC-1 CM 介导的基因和蛋白质水平的细胞外基质、细胞因子和粘附分子的激活。此外，与 shRNA 对照 (shCTR) PSC 相比，shITGA11 hPSC 的迁移和收缩性降低。此外，我们研究了 ITGA11 对 hPSC 旁分泌效应的影响。有趣的是，用 TGF-β 或 PANC-1 CM 激活的 shITGA11 hPSC 的 CM 导致肿瘤细胞的迁移和侵袭能力低于其对照，激活的 shCTR hPSC。总之，这项研究提出 ITGA11 是一个有趣的基质治疗靶点，它在调节 PSC 分化为 CAF 和旁分泌效应中起着关键作用。- Schnittert, J., Bansal, R., Mardhian, D. F., van Baarlen, J., Östman, A., Prakash, J. Integrin α11 在胰腺星状细胞中调节胰腺癌细胞中的肿瘤基质相互作用。
